33

Given these results, some patients may receive extended durations of DAPT if they

have a previous history of prior MI, or are post-PCI and have received a DES.

Anti-Ischemic Pharmacotherapy

Historically, agents used in the treatment of patients with chronic stable angina

primarily affected either determinants of myocardial oxygen supply, myocardial

oxygen demand, or both. Within this paradigm, β-blockers, CCBs, and chronic nitrate

therapy have demonstrated effectiveness in the prevention of ischemic symptoms. In

January 2006, the US Food and Drug Administration (FDA) granted approval to

ranolazine, representing the first new class of agents to be approved for the treatment

of chronic stable angina in the last 20 years. Unlike traditional anti-anginal

medications, ranolazine does not affect heart rate or BP. The selection of specific

anti-ischemic pharmacotherapy for patients with chronic stable angina should take

into account relevant patient characteristics as well as guideline recommendations.

β-BLOCKERS

β-Blockers lower myocardial oxygen demand primarily by lowering heart rate and

myocardial contractility. Neither β-selectivity nor the presence of α-1 blockade

appear to vary efficacy at preventing ischemia and, therefore, the choice of a specific

agent for a given patient will likely depend on cost, number of daily doses, and the

presence of other comorbid conditions. β-Blockers with intrinsic sympathomimetic

activity are not routinely used in patients with stable angina due to reduced efficacy.

The dose of the β-blocker should be titrated to a goal resting heart rate of 55 to 60

beats/minute and therefore will be patient specific.

34 β-Blockers should be avoided

in patients with primary vasospastic angina and may worsen symptoms in patients

with reactive airway disease or PAD. The most common side effects observed with

chronic therapy include bradycardia, hypotension, fatigue, and sexual dysfunction.

Other conditions that may prevent the use of β-blocker therapy include severe

bradycardia or atrioventricular (AV) nodal conduction defects.

35–37

NITRATES

Nitrates are available in a number of different formulations and available options are

listed in Table 12-4. Regardless of the formulation, all nitrate options are effective at

preventing or relieving ischemic symptoms if used appropriately, including the use of

a nitrate-free interval. Nitrates can increase myocardial oxygen supply through

vasodilation of the coronary arteries, as well as reduce myocardial oxygen demand

through the reduction of preload. Nitrates produce vasodilation through the

biotransformation and the release of NO.

38 Long-acting nitrates are effective agents

for the prevention of anginal symptoms. Sublingual NTG is a vital agent to treat acute

anginal attacks. Common side effects of nitrate therapy include hypotension,

dizziness, and headache. Headache often will resolve with continued therapy and

may be treated with acetaminophen. Concomitant administration with

phosphodiesterase type 5 inhibitors (within 24 hours for sildenafil and vardenafil, 48

hours for tadalafil) is contraindicated due to the risk of life-threatening

hypotension.

38,39

CALCIUM-CHANNEL BLOCKERS

CCBs are highly diverse compounds. They differ markedly in chemical structure as

well as specificity for cardiac and peripheral tissue. Using these characteristics, it is

possible to classify CCBs into several major types (Table 12-5).

40

Both non-dihydropyridine CCBs (non-DHP CCBs), diltiazem and verapamil, exert

similar effects on myocardial and peripheral tissue. They slow conduction and

prolong the refractory period in the AV node (see Chapter 15, Cardiac Arrhythmias).

Both agents can depress myocardial contractility and are moderate peripheral

vasodilators and potent coronary artery vasodilators.

40

In contrast to diltiazem or verapamil, the dihydropyridines (DHPs) such as

nifedipine, amlodipine, felodipine, isradipine, and nicardipine do not slow cardiac

conduction. They are more potent peripheral vasodilators and may be associated

with a reflex increase in the heart rate. All DHPs have negative inotropic effects in

vitro, but these effects, clinically, are overshadowed by the reflex sympathetic

activation and decreased afterload. The net effect of these actions results in no or

minimal depression of myocardial function (see Chapter 14, Heart Failure).

40

Both DHP and non-DHP CCBs produce an increase in myocardial oxygen supply

through vasodilation of the coronary arteries, as well as reduce myocardial oxygen

demand through lowering of intramyocardial wall tension (by lowering systemic BP).

However, non-DHP CCBs would be expected to lower myocardial oxygen demand

to a greater degree because of additional reductions in heart rate and contractility.

Although defined as being within the same pharmacologic class, it is important to

consider DHPs and non-DHPs separately when considering their use in patients with

chronic stable angina. The reductions in heart rate and contractility with non-DHPs

may be beneficial for some patients, although detrimental in others such as patients

with compromised left ventricular (LV) function or bradycardia at baseline.

Conversely, amlodipine and felodipine have been shown to be safe to use in patients

with LV dysfunction and to provide a reasonable option for the prevention of

ischemic symptoms in those patients.

40 CCB should be used cautiously when used in

combination with cyclosporine, carbamazepine, lithium, amiodarone, and digoxin.

Non-DHP CCB should be avoided in most situations due to the duplicate effects on

heart rate and cardiac contractility.

1 Side effects of CCB therapy depend on the

specific agent used. Use of non-DHP CCBs may result in bradycardia, hypotension,

and AV block. Patients receiving DHP CCBs may experience reflex tachycardia,

peripheral edema, headache, and hypotension.

40

RANOLAZINE

Ranolazine is an anti-ischemic agent that inhibits the late sodium current, thereby

reducing intracellular sodium. During myocardial ischemia, sodium influx is

increased, leading to intracellular calcium overload through the sodium/calcium

exchanger. An excess of intracellular calcium leads to changes that promote and

worsen ischemia, such as increased intramyocardial wall tension and reduced

microvascular perfusion. By inhibiting sodium influx, ranolazine prevents ischemiainduced contractile dysfunction and delays the onset of angina. A key distinction

between ranolazine and traditional antianginal agents is that it has no appreciable

effect on heart rate and BP. The lack of significant hemodynamic effects makes the

drug useful in patients in need of further antianginal therapy but who have low BP or

heart rates preventing titration of conventional antianginal agents.

41

p. 214

p. 215

Table 12-4

Commonly Prescribed Organic Nitrates

Drug Dosage Form Duration

Onset

(minutes) Usual Dosage

Short-Acting

NTG SL 10–30 minutes 1–3 0.4–0.6 mg

a

,

b

NTG Translingualspray 10–30 minutes 2–4 0.4 mg/metered spray

a

,

b

NTG IV 3–5 minutes

c 1–2 Initially 5 mcg/minute. Increase every

3–5 minutes until pain is relieved or

hypotension occurs

Long-Acting

d

NTG SR capsule 4–8 hours 30 6.5–9 mg every 8 hours

NTG Topical ointment

e 4–8 hours 30 1–2 inches every 4–6 hours

f

NTG Transdermal patch 4–>8 hours 30–60 0.1–0.2 mg/h to start; titrate up to 0.8

mg/hour

f

NTG Transmucosal 3–6 hours 2–5 1–3 mg every 3–5 hours

f

ISDN SL 2–4 hours 2–5 2.5–10 mg every 2–4 hours

f

Chewable 2–4 hours 2–5 5–10 mg every 2–4 hours

f

Oral 2–6 hours 15–40 10–60 mg every 4–6 hours

f

SR capsule 4–8 hours 15–40 40–80 mg every 6–8 hours

f

ISMN

g Tablet (ISMO,

Monoket)

7–8 hours 30–60 10–20 mg BID (morning and midday)

to start; titrate to 20–40 mg BID

f

Extended-release

tablet (Imdur)

8–12 hours 30–60 60 mg every day to start; titrate to

30–120 mg every day

aWhen using sublingual or translingual spray forms of NTG, patients should administer the dose while sitting to

minimize tachycardia, hypotension, dizziness, headache, and flushing. The optimal dose relieves symptoms with

<10- to 15-mm Hg drop in systolic blood pressure or <10-beats/minute rise in pulse. Pain relief is rapid (onset 1–2

minutes; relief in 3–5 minutes), but up to three doses at 5-minute intervals may be given. After this, medical

assistance should be summoned.

bSublingual NTG tablets are degraded rapidly by heat, moisture, and light. They should be stored in a cool, dry

place; do not leave the lid open or refrigerate. Tablets should be stored in the original manufacturer’s container or

a glass vial because the tablets volatilize and bind to many plastic vials and cotton. Previously, stinging of the

tongue was an indicator of fresh tablets, but newer formulations only cause stinging in ∼75% of patients.

cDuration after infusion discontinued.

dLonger-acting forms of nitrates are effective drugs, but it is important to understand their limitations to optimize

effectiveness. Sublingual ISDN tablets display an onset and duration intermediate between that of sublingual NTG

and oral ISDN. Because of high presystemic (first-pass) metabolism of the oral forms of both NTG and ISDN,

very large doses may be required compared with SL or chewable dosage forms. Small oral doses (2.5 mg NTG, 5

mg ISDN) are probably not effective; doses as large as 9 mg NTG and 60 mg ISDN are not uncommon. Despite

claims for longer activity, ointments and oral forms are often only effective for 4–8 hours, even when given as SR

preparations. Also, continued daily use leads to rapid development of tolerance (see note f).

eSqueeze 1–2 inches of ointment onto the calibrated paper enclosed in the package with tube. Carefully spread the

ointment on chest in a thin layer ˜2 inches by 2 inches in size. Keep area covered with applicator paper. Wipe off

previous dose before adding new dose or if hypotensive. If another person applies the ointment, avoid contact with

fingers or eyes to prevent headache or hypotension.

fDosage regimens should maintain a nitrate-free interval (e.g., bedtime) to decrease tolerance development. Give

last oral dose or remove ointment or transdermal patch at 7 PM. Give last dose of SR ISDN in early afternoon.

gMajor active metabolite of ISDN; 100% bioavailable; no first-pass metabolism, but tolerance may still occur.

Rapid-release form (ISMO, Monoket) as 10- and 20-mg tablets. Extended-release form (Imdur) as 60-mg tablets.

Okay to cut Indur in half, do not crush or chew.

BID, 2 times daily; ISDN, isosorbide dinitrate; ISMN, isosorbide monohydrate; IV, intravenous; NTG,

nitroglycerin; SL, sublingual; SR, sustained-release.

Initial clinical trials demonstrated that ranolazine was an effective agent at

reducing anginal episodes when added to existing therapy with CCBs or long-acting

nitrates. Subsequent investigations demonstrated long-term safety and efficacy, and

the agent may be considered at any stage in the treatment of chronic stable angina.

Common adverse effects include headache, constipation, dizziness, and nausea. The

drug is extensively metabolized in the liver through both cytochrome P-450 enzymes

CYP3A4 and CYP2D6; therefore, attention should be paid to potential drug

interactions. CYP3A4 appears to be the major pathway for metabolism and use of

ranolazine is contraindicated in patients with significant hepatic dysfunction and in

those receiving potent inhibitors and inducers of CYP3A4 such as ketoconazole or

rifampin, respectively. Ranolazine is contraindicated in patients receiving many of

the available antiretroviral agents.

41

Myocardial Revascularization

Revascularization of the myocardium, with CABG or PCI, is a mainstay in the

treatment of patients with CAD. The goals of revascularization do not differ from the

overall goals in treating patients with chronic stable angina, namely, to relieve

symptoms, improve quality of life, and prevent MI and death. Historically, a great

deal of focus was devoted to comparing CABG, PCI, and medical management and

their relative efficacy in relieving symptoms and improving prognosis. In a broad

population of patients with CAD, revascularization with either CABG or PCI was

found to be superior to medical management therapy alone at relieving symptoms at 1

year, although there was no difference in overall mortality between the treatment

strategies.

42 However, CABG therapy tended to be superior at providing long-term

relief of symptoms, as well as providing a lower need for repeat revascularization

therapy compared to PCI. When considering subgroups of patients with more severe

disease or who have manifested left ventricular dysfunction, differences in long-term

mortality can be observed among the different treatment strategies. In patients with

double-vessel or triple-vessel disease, significant disease of the left main artery, or

left ventricular dysfunction, CABG therapy has been demonstrated to provide a

reduced 5-year mortality rate compared with PCI or medical therapy alone.